NAD-metabolism som mål för neuroskydd vid åldersrelaterad oftalmiska och neurodegenerativa sjukdomar

Background: We have discovered metabolic and mitochondrial dysfunction in the retina and optic nerve which occur prior to neurodegeneration in glaucoma. One of these early changes is a decline in the important metabolite NAD which critically regulates neuronal survival in glaucoma. Preventing NAD decline pharmacologically or through targeted gene therapies robustly prevents neurodegeneration. We are now actively generating novel NAD-generating compounds based on our initial studies.

Issue: Glaucoma affects 2% of the Nordic population. It is a huge health and economic burden. There are no neuroprotective therapies. 42% of glaucoma patients will go blind in at least one eye.

5-year work plan: (1) Development of novel small molecules and selection of lead compound(s); (2) In silico modelling of NMNAT2 and MST to assess NMNAT2 binding; (3) Optimize dosage and delivery route / carrier for novel small molecules; (4) Test NMNAT2-specificity of novel small molecules; (5) Safety / toxicity testing of select lead small molecule; (6) Long-term testing of novel small molecules in in vitro and in vivo systems (this will be the focus of this Ögonfonden application).

Meaning: Neuronal NAD production is an ideal target for neuroprotective drug discovery for neuroprotection in glaucoma and other axon degenerations.